Development and implementation of the population Fisher information matrix for the evaluation of population pharmacokinetic designs.

In population pharmacokinetic studies, the precision of parameter estimates is dependent on the population design. Methods based on the Fisher information matrix have been developed and extended to population studies to evaluate and optimize designs. In this paper we propose simple programming tools to evaluate population pharmacokinetic designs. This involved the development of an expression for the Fisher information matrix for nonlinear mixed-effects models, including estimation of the variance of the residual error. We implemented this expression as a generic function for two software applications: S-PLUS and MATLAB. The evaluation of population designs based on two pharmacokinetic examples from the literature is shown to illustrate the efficiency and the simplicity of this theoretic approach. Although no optimization method of the design is provided, these functions can be used to select and compare population designs among a large set of possible designs, avoiding a lot of simulations.

Time-dependent master equation simulation of complex elementary reactions in combustion: Application to the reaction of (CH2)-C-1 with C2H2 from 300-2000 K

Computational simulations of the title reaction are presented, covering a temperature range from 300 to 2000 K. At lower temperatures we find that initial formation of the cyclopropene complex by addition of methylene to acetylene is irreversible, as is the stabilisation process via collisional energy transfer. Product branching between propargyl and the stable isomers is predicted at 300 K as a function of pressure for the first time. At intermediate temperatures (1200 K), complex temporal evolution involving multiple steady states begins to emerge. At high temperatures (2000 K) the timescale for subsequent unimolecular decay of thermalized intermediates begins to impinge on the timescale for reaction of methylene, such that the rate of formation of propargyl product does not admit a simple analysis in terms of a single time-independent rate constant until the methylene supply becomes depleted. Likewise, at the elevated temperatures the thermalized intermediates cannot be regarded as irreversible product channels. Our solution algorithm involves spectral propagation of a symmetrised version of the discretized master equation matrix, and is implemented in a high precision environment which makes hitherto unachievable low-temperature modelling a reality.

Analytical validation for a series of marker compounds used to assess renal drug elimination processes

Renal drug elimination is determined by glomerular filtration, tubular secretion, and tubular reabsorption. Changes in the integrity of these processes influence renal drug clearance, and these changes may not be detected by conventional measures of renal function such as creatinine clearance. The aim of the current study was to examine the analytic issues needed to develop a cocktail of marker drugs (fluconazole, rac-pindolol, para-aminohippuric acid, sinistrin) to measure simultaneously the mechanisms contributing to renal clearance. High-performance liquid chromatographic methods of analysis for fluconazole, pindolol, para-aminohippuric acid, and creatinine and an enzymatic assay for sinistrin were developed or modified and then validated to allow determination of each of the compounds in both plasma and urine in the presence of all other marker drugs. A pilot clinical study in one volunteer was conducted to ensure that the assays were suitable for quantitating all the marker drugs to the sensitivity and specificity needed to allow accurate determination of individual renal clearances. The performance of all assays (plasma and urine) complied with published validation criteria. All standard curves displayed linearity over the concentration ranges required, with coefficients of correlation greater than 0.99. The precision of the interday and intraday variabilities of quality controls for each marker in plasma and urine were all less than 11.9% for each marker. Recoveries of markers (and internal standards) in plasma and urine were all at least 90%. All markers investigated were shown to be stable when plasma or urine was frozen and thawed. For all the assays developed, there were no interferences from other markers or endogenous substances. In a pilot clinical study, concentrations of all markers could be accurately and reproducibly determined for a sufficient duration of time after administration to calculate accurate renal clearance for each marker. This article presents details of the analytic techniques developed for measuring concentrations of marker drugs for different renal elimination processes administered as a single dose to define the processes contributing to renal drug elimination.

An evaluation of two indices of red fox (Vulpes vulpes) abundance in an arid environment

The suitability of spotlight counts to index red fox abundance was assessed in an arid environment through a comparison with a scat deposition index (active attractant). In most cases there was a high degree of correlation between the two indices, suggesting that the spotlight counts were accurately documenting fluctuations in population size. However, the precision of the spotlight index was often low (c.v. = 0.07-0.46), suggesting that the technique may not allow the statistical detection of small changes in abundance. During periods when there was an influx of new individuals into the population, the seasonal scat index displayed a three-month time lag in documenting abundance while foxes accustomed themselves to the presence of the regular food supply. The level of precision of the scat index was also found to be relatively low (c.v. = 0.21-0.48). Nevertheless, further refinements of this technique may produce a suitable measure of fox abundance.

Impact of malocclusion and orthognathic reconstruction surgery on resonance and articulatory function: an examination of variability in five cases

Articulatory patterns and nasal resonance were assessed before and 6 months after orthognathic reconstruction surgery in five patients with dentofacial deformities. Perceptual and physiological assessments showed disorders of nasality and articulatory function preoperatively, two patients being hyponasal, and one hypernasal. Four patients had mild articulatory deficits, and four had reduced maximal lip or tongue pressures. Operation resulted in different patterns of change. Nasality deteriorated in three patients and articulatory precision and intelligibility improved in only one patient and showed no change in the other four. Operation improved interlabial pressures in three patients, while its impact on tongue pressures varied, being improved in one case, deteriorating in one, and remaining unchanged in the other three. The variability in the results highlights the need for routine assessment of speech and resonance before and after orthognathic reconstruction. (C) 2002 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Science Ltd. All rights reserved.

Repeatability of surface EMG variables in the sternocleidomastoid and anterior scalene muscles

In this study we examined the repeatability and reliability of the surface electromyographic (sEMG) signal mean frequency (MNF), average rectified value (ARV) and conduction velocity (CV) measured for the sternocleidomastoid (SCM) and the anterior scalene (AS) muscles in nine healthy volunteers during 15-s isometric cervical flexion contractions at 50% of the maximal voluntary contraction level over 3 non-consecutive days. Repeatability and reliability estimates were obtained for the initial values and rates of change of each sEMG variable by using both the Intraclass Correlation Coefficient (ICC) and the normalised standard error of the mean (nSEM). Results from SCM indicated good levels of repeatability for the initial value and slope of ARV (ICC > 65%). For the AS, high levels of repeatability were identified for the initial value of MNF (ICC > 70%) and the slope of ARV (ICC > 75%). Values of nSEM in the range 2.8-7.2% were obtained for the initial values of MNF and CV for both SCM and AS, indicating clinically acceptable measurement precision. The low value obtained for the nSEM of the initial value of MNF for the AS, in combination with the high ICC, indicates that of all of the variables examined, this variable could offer the best normative index to distinguish between subjects with and without neck pain, and represents the sEMG variable of choice for future evaluation purposes.

The Building Partnerships Program: An Approach to Community-based Learning for Medical Students in Australia

The Building Partnerships Program at the University of Queensland, Australia seeks to address the dual challenge of preparing doctors who are responsive to the community while providing a meaningful context for social sciences learning. Through partnerships with a diverse range of community agencies, the program offers students opportunities to gain non-clinical perspectives on health and illness through structured learning activities including: family visits; community agency visits and attachments; and interview training. Students learn first-hand about psychosocial influences on health and how people manage health problems on a day-to-day basis. They also gain insights into the work of community agencies and how they as future doctors might work in partnership with them to enhance patient care. We outline the main components of the program, identify challenges and successes from student and community agency perspectives, and consider areas that invite further development.

Ar-40/-Ar-39 geochronology at the Instituto de Geociencias, USP: instrumentation, analytical procedures, and calibration

Laser heating Ar-40/Ar-39 geochronology provides high analytical precision and accuracy, mum-scale spatial resolution. and statistically significant data sets for the study of geological and planetary processes, A newly commissioned Ar-40/Ar-39 laboratory at CPGeo/USP, Sao Paulo, Brazil, equips the Brazilian scientific community with a new powerful tool applicable to the study of geological and cosmochemical processes. Detailed information about laboratory layout, environmental conditions, and instrumentation provides the necessary parameters for the evaluation of the CPGeo/USp Ar-40/Ar-39 suitability to a diverse range of applications. Details about analytical procedures, including mineral separation, irradiation at the IPEN/CNEN reactor at USP, and mass spectrometric analysis enable potential researchers to design the necessary sampling and sample preparation program suitable to the objectives of their study. Finally, the results of calibration tests using Ca and K salts and glasses, international mineral standards, and in-house mineral standards show that the accuracy and precision obtained at the Ar-40/Ar-39 laboratory at CPGeo/USP are comparable to results obtained in the most respected laboratories internationally. The extensive calibration and standardization procedures under-taken ensure that the results of analytical studies carried out in our laboratories will gain immediate international credibility, enabling Brazilian students and scientists to conduct forefront research in earth and planetary sciences.

Application of spatial analysis techniques to adjust for fertility trends and identify interplot competition in early stage sugarcane selection trials

Most sugarcane breeding programs in Australia use large unreplicated trials to evaluate clones in the early stages of selection. Commercial varieties that are replicated provide a method of local control of soil fertility. Although such methods may be useful in detecting broad trends in the field, variation often occurs on a much smaller scale. Methods such as spatial analysis adjust a plot for variability by using information from immediate neighbours. These techniques are routinely used to analyse cereal data in Australia and have resulted in increased accuracy and precision in the estimates of variety effects. In this paper, spatial analyses in which the variability is decomposed into local, natural, and extraneous components are applied to early selection trials in sugarcane. Interplot competition in cane yield and trend in sugar content were substantial in many of the trials and there were often large differences in the selections between the spatial and current method used by the Bureau of Sugar Experiment Stations. A joint modelling approach for tonnes sugar per hectare in response to fertility trends and interplot competition is recommended.

Evaluating two morningness scales with item response theory

Using a student sample (n = 692) and an organization sample (n = 180), we scrutinized two morning-evening orientation scales using item response theory (IRT) methods. We used IRT to compare the measurement precision of the Composite Scale (CS) and the Early/Late Preferences Scale (PS). The CS had slightly higher measurement precision at all ranges of orientations, except for extreme morning and evening orientations for which the PS had slightly higher precision. IRT item-level statistics were also computed to try to understand how morning-orientation items functioned. Items that asked questions about morning activities tended to be more discriminating indicators of morning-orientation than items that asked about evening or peak performance activities. Items that involved unpleasant activities were less frequently endorsed than items that involved neutral or enjoyable activities. Implications for measurement of morning-evening orientation are discussed. (C) 2002 Elsevier Science Ltd. All rights reserved.

New W-isotope evidence for rapid terrestrial accretion and very early core formation

The short-lived Hf-182-W-182-isotope system is an ideal clock to trace core formation and accretion processes of planets. Planetary accretion and metal/silicate fractionation chronologies are calculated relative to the chondritic Hf-182-W-182-isotope evolution. Here, we report new high-precision W-isotope data for the carbonaceous chondrite Allende that are much less radiogenic than previously reported and are in good agreement with published internal Hf-W chronometry of enstatite chondrites. If the W-isotope composition of terrestrial rocks, representing the bulk silicate Earth, is homogeneous and 2.24 epsilon(182W) units more radiogenic than that of the bulk Earth, metal/silicate differentiation of the Earth occurred very early. The new W-isotope data constrain the mean time of terrestrial core formation to 34 million years after the start of solar system accretion. Early terrestrial core formation implies rapid terrestrial accretion, thus permitting formation of the Moon by giant impact while Hf-182 was still alive. This could explain why lunar W-isotopes are more radiogenic than the terrestrial value. Copyright (C) 2002 Elsevier Science Ltd.

MR image-based measurement of rates of change in volumes of brain structures. Part 1: Method and validation

A detailed analysis procedure is described for evaluating rates of volumetric change in brain structures based on structural magnetic resonance (MR) images. In this procedure, a series of image processing tools have been employed to address the problems encountered in measuring rates of change based on structural MR images. These tools include an algorithm for intensity non-uniforniity correction, a robust algorithm for three-dimensional image registration with sub-voxel precision and an algorithm for brain tissue segmentation. However, a unique feature in the procedure is the use of a fractional volume model that has been developed to provide a quantitative measure for the partial volume effect. With this model, the fractional constituent tissue volumes are evaluated for voxels at the tissue boundary that manifest partial volume effect, thus allowing tissue boundaries be defined at a sub-voxel level and in an automated fashion. Validation studies are presented on key algorithms including segmentation and registration. An overall assessment of the method is provided through the evaluation of the rates of brain atrophy in a group of normal elderly subjects for which the rate of brain atrophy due to normal aging is predictably small. An application of the method is given in Part 11 where the rates of brain atrophy in various brain regions are studied in relation to normal aging and Alzheimer's disease. (C) 2002 Elsevier Science Inc. All rights reserved.

Computational differentiation of N-terminal signal peptides and transmembrane helices

Signal peptides and transmembrane helices both contain a stretch of hydrophobic amino acids. This common feature makes it difficult for signal peptide and transmembrane helix predictors to correctly assign identity to stretches of hydrophobic residues near the N-terminal methionine of a protein sequence. The inability to reliably distinguish between N-terminal transmembrane helix and signal peptide is an error with serious consequences for the prediction of protein secretory status or transmembrane topology. In this study, we report a new method for differentiating protein N-terminal signal peptides and transmembrane helices. Based on the sequence features extracted from hydrophobic regions (amino acid frequency, hydrophobicity, and the start position), we set up discriminant functions and examined them on non-redundant datasets with jackknife tests. This method can incorporate other signal peptide prediction methods and achieve higher prediction accuracy. For Gram-negative bacterial proteins, 95.7% of N-terminal signal peptides and transmembrane helices can be correctly predicted (coefficient 0.90). Given a sensitivity of 90%, transmembrane helices can be identified from signal peptides with a precision of 99% (coefficient 0.92). For eukaryotic proteins, 94.2% of N-terminal signal peptides and transmembrane helices can be correctly predicted with coefficient 0.83. Given a sensitivity of 90%, transmembrane helices can be identified from signal peptides with a precision of 87% (coefficient 0.85). The method can be used to complement current transmembrane protein prediction and signal peptide prediction methods to improve their prediction accuracies. (C) 2003 Elsevier Inc. All rights reserved.

An advanced method for eliminating impacts from frequency deviations in power system signal processing

Frequency deviation is a common problem for power system signal processing. Many power system measurements are carried out in a fixed sampling rate assuming the system operates in its nominal frequency (50 or 60 Hz). However, the actual frequency may deviate from the normal value from time to time due to various reasons such as disturbances and subsequent system transients. Measurement of signals based on a fixed sampling rate may introduce errors under such situations. In order to achieve high precision signal measurement appropriate algorithms need to be employed to reduce the impact from frequency deviation in the power system data acquisition process. This paper proposes an advanced algorithm to enhance Fourier transform for power system signal processing. The algorithm is able to effectively correct frequency deviation under fixed sampling rate. Accurate measurement of power system signals is essential for the secure and reliable operation of power systems. The algorithm is readily applicable to such occasions where signal processing is affected by frequency deviation. Both mathematical proof and numerical simulation are given in this paper to illustrate robustness and effectiveness of the proposed algorithm. Crown Copyright (C) 2003 Published by Elsevier Science B.V. All rights reserved.

API documentation with executable examples

The rise of component-based software development has created an urgent need for effective application program interface (API) documentation. Experience has shown that it is hard to create precise and readable documentation. Prose documentation can provide a good overview but lacks precision. Formal methods offer precision but the resulting documentation is expensive to develop. Worse, few developers have the skill or inclination to read formal documentation. We present a pragmatic solution to the problem of API documentation. We augment the prose documentation with executable test cases, including expected outputs, and use the prose plus the test cases as the documentation. With appropriate tool support, the test cases are easy to develop and read. Such test cases constitute a completely formal, albeit partial, specification of input/output behavior. Equally important, consistency between code and documentation is demonstrated by running the test cases. This approach provides an attractive bridge between formal and informal documentation. We also present a tool that supports compact and readable test cases; and generation of test drivers and documentation, and illustrate the approach with detailed case studies. (C) 2002 Elsevier Science Inc. All rights reserved.